Molecular cloning and characterization of the GATA1 cofactor human FOG1 and assessment of its binding to GATA1 proteins carrying D218 substitutions
Molecular cloning and characterization of the GATA1 cofactor human FOG1 and assessment of its binding to GATA1 proteins carrying D218 substitutions
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DOI：
10.1007/s00439-002-0832-1
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发表时间：
2003-01-01
期刊：
影响因子：
5.3
通讯作者：
Van Geet, C
中科院分区：
文献类型：
--
作者：
Freson, K;Thys, C;Van Geet, C
红系和巨核系的分化和成熟是通过转录因子GATA1及其基本辅因子GATA1之友(FOG1)之间的合作来调节的。这两种小鼠蛋白之间的相互作用在体外得到了很好的研究，并依赖于Fog1与GATA1的N-末端锌指(N-Finger)的结合。我们在染色体16q24上发现了人类FOG1基因，并发现FOG1基因主要在造血细胞中表达，也在其他几个组织中表达。序列分析显示，FOG1蛋白由1006个氨基酸组成，含有9个锌指，与小鼠的Fog1指高度同源。然而，人和小鼠手指5的氨基酸序列和GATA1结合能力不同。体外结合研究表明，FOG1与GATA1和GATA2都有相互作用。我们和其他人描述了GATA1 N-Finger(V205M、D218G、D218Y或G208S)突变的患者，他们患有大血小板减少症和红细胞异常。我们现在在体外表明，携带D218 GATA1突变的患者的血小板和红细胞中GATA1和FOF1之间的相互作用确实受到干扰。人类FOG1基因的鉴定将使非X连锁血小板减少和红细胞生成障碍患者的基因筛查成为可能。
Erythroid and megakaryocytic lineage differentiation and maturation are regulated via cooperation between transcription factor GATA1 and its essential cofactor friend-of-GATA1 (FOG1). The interaction between these two murine proteins is well studied in vitro and depends on the binding of Fog1 to the N-terminal zinc finger (N-finger) of Gata1. We identified the human FOG1 gene on chromosome 16q24 and found expression mainly in hematopoietic cells and also in several other tissues. Sequencing of FOG1 cDNA revealed a 1006 amino-acid protein that contained nine zinc fingers, highly homologous to murine Fog1 fingers. The amino acid sequence and the GATA1-binding capacity of the human and murine finger 5 are however different. Ex vivo binding studies demonstrated that FOG1 interacts with both GATA1 and GATA2. We and others have described patients with mutations in the GATA1 N-finger (V205 M, D218G, D218Y, or G208S), who suffer from macrothrombocytopenia and erythrocyte abnormalities. We now show ex vivo that the interaction between GATA1 and FOG 1 is indeed disturbed in platelets and erythrocytes of those patients carrying D218 GATA1 mutations. The identification of the human FOG1 gene will enable the genetic screening of patients with non X-linked thrombocytopenia and dyserythropoiesis.